This application is an RO3 for an HIV, AIDS and related illnesses international research collaboration award. The overall aim of this work is to define the specific mechanisms involved in host defense against cryptococcosis with a view to developing new immunotherapeutic approaches to treatment and prevention. This proposal centers on one such novel approach: the use of chloroquine as an immunomodulating agent to treat AIDS-related cryptococcosis and the potential of combined therapy with chloroquine and monoclonal anticapsular antibody. In experiments examining the role of iron deprivation in macrophage inhibition of C. neoformans, chloroquine was found to markedly enhance the anticryptococcal activity of monocyte-derived macrophages (MDM), although the mechanism was independent of iron. This proposal builds on these initial observations. Monoclonal antibodies against the capsular polysaccharide of C. neoformans are potent opsonins and may further enhance the effect of chloroquine, which depends on the organism being internalized. Specifically, these studies will: 1) determine the effect of chloroquine +/- anticapsular antibody on the anticryptococcal activity of human monocytes, MDM, and bronchoalveolar macrophages; examine the mechanism by which chloroquine enhances the effector function of macrophages against C. neoformans; and determine if chloroquine, at the concentrations required to enhance effector function, also alters afferent macrophage responses to C. neoformans; and 2) test the efficacy of chloroquine +/- anticapsular antibody in murine cryptococcosis following intravenous and intratracheal inoculation, after establishment of meningeal infection, and in combination with antifungal therapy. In addition to outbred mice, T cell deficient nude mice will be used to reflect the immunocompromise of AIDS patients.